The unifying theme of this Center is that schizophrenia reflects an impaired interaction between the dopaminergic and glutamatergic systems of the striatum and the PFC. In addressing this theme this project of this Center will test the idea that many of the symptoms of schizophrenia can be traced to three specifc defects: 1) Striatal dopaminergic hyperactivity 2) Cortical dopaminergic dysregulation and 3) Cortical glutamatergic hypofunction. The hypotheses will be tested using genetically engineered, selective molecular alterations that are both regionally and temporally specific. The objective is to establish specific cause-effect relationships that may help to explain symptoms of schizophrenia. Hypothesis 1 is tested in mice with increased striatal DA D2 receptor expression (aim 1). Hypothesis 2 is investigated in mice with increased neocortical DA D1 receptor expression and decreased DA prefrontal innervation (aim 2) and hypothesis 3 is tested in mice expressing mutant NMDA receptors selectively in D1 receptor positive cells of the neocortex (aim 3). All three mouse models will be used to study a) the behavioral consequences of the genetic modifications with emphasis on: cognitive impairments such as deficits in working memory and behavioral flexibility by the physiological Consequences that may explain Cognitive impairments, c) how cortical and subcortical glutamatergic and dopaminergic systems interact and d) whether there are chronic effects of these modifications that:may lead to neurodevelopmentai abnormalities. Point a) wili be addressed using behavioral methods, point b) using functional imaging and electrophysiological techniques, poim c) using microdiatysis and electrophysiological techniques and point d) using structural brain imaging, stereological measurements and various molecular and biochemical methods including gene expression analysis. First results obtained with mice that over-express DA D2 receptors selectively in the striatum show deficits in working memory tasks. This has two important implications. First, it suggests that subcortical striatal D2 receptors may affect the function of the PFC and second, it suggests that the striatum and its D2 receptors may be more critical for cognitive impairments of schizophrenic patients than it has generally been assumed. The results of the proposed studies will lead to the development of clinical hypotheses that can be subsequently tested in patients.